The present invention relates generally to methods for treating and preventing multiple sclerosis by using peptide analogues of human myelin basic protein.
Multiple sclerosis (MS) is a chronic, inflammatory disease that affects approximately 250,000 individuals in the United States. Although the clinical course may be quite variable, the most common form is manifested by relapsing neurological deficits, in particular, paralysis, sensory deficits, and visual problems.
The inflammatory process occurs primarily within the white matter of the central nervous system and is mediated by T lymphocytes, B lymphocytes, and macrophages. These cells are responsible for the demyelination of axons. The characteristic lesion in MS is called the plaque due to its macroscopic appearance.
Multiple sclerosis is thought to arise from pathogenic T cells that somehow evaded mechanisms establishing self-tolerance, and attack normal tissue. T cell reactivity to myelin basic protein may be a critical component in the development of MS. The pathogenic T cells found in lesions have restricted heterogeneity of antigen receptors (TCR). The T cells isolated from plaques show rearrangement of a restricted number of Vxcex1 and Vxcex2 gene segments. In addition, the TCRs display several dominant amino acid motifs in the third complementarity determining region (CDR), which is the major antigen contact site. All together, three CDR3 motifs have been identified in T cell clones known to recognize an epitope within amino acids 86-106 of myelin basic protein. These motifs were found in 44% of rearranged TCR sequences involving one particular Vxcex2 gene rearranged in T cells isolated from brain of two patients with MS.
A definitive treatment for MS has not been established. Historically, corticosteroids and ACTH have been used to treat MS. Basically, these drugs reduce the inflammatory response by toxicity to lymphocytes. Recovery may be hastened from acute exacerbations, but these drugs do not prevent future attacks or prevent development of additional disabilities or chronic progression of MS (Carter and Rodriguez, Mayo Clinic Proc. 64:664, 1989; Weiner and Hafler, Ann. Neurol. 23:211, 1988). In addition, the substantial side effects of steroid treatments make these drugs undesirable for long-term use.
Other toxic compounds, such as azathioprine, a purine antagonist, cyclophosphamide, and cyclosporine have been used to treat symptoms of MS. Like corticosteroid treatment, these drugs are beneficial at most for a short term and are highly toxic. Side effects include increased malignancies, leukopenias, toxic hepatitis, gastrointestinal problems, hypertension, and nephrotoxicity (Mitchell, Cont. Clin. Neurol. 77:231, 1993; Weiner and Hafler, supra). Antibody based therapies directed toward T cells, such as anti-CD4 antibodies, are currently under study for treatment of MS. However, these agents may cause deleterious side effects by immunocompromising the patient.
More recently, cytokines such as IFN-xcex3 and IFN-xcex2 have been administered in attempts to alleviate the symptoms of MS. However, a pilot study involving IFN-xcex3 was terminated because 7 of 18 patients treated with this drug experienced a clinical exacerbation within one month after initiation of treatment. Moreover, there was an increase in the specific response to MBP (Weiner and Hafler, supra).
Betaseron, a modified beta interferon, has recently been approved for use in MS patients. Although Betaseron treatment showed some improvement in exacerbation rates (Paty et al., Neurology 43:662, 1993), there was no difference in the rate of clinical deterioration between treated and control groups (IFNB MS Study Group, Neurology 43:655, 1993; Paty et al., supra). Side effects were commonly observed. The most frequent of such side effects were fever (40%-58% of patients), flu-like symptoms (76% of patients), chills (46% of patients), mylagias (41% of patients), and sweating (23% of patients). In addition, injection site reactions (85%), including inflammation, pain, hypersensitivity and necrosis, were common (IFNB MS Study Group, supra; Connelly, Annals of Pharm. 28:610, 1994).
In view of the problems associated with existing treatments of MS, there is a compelling need for improved treatments which are more effective and are not associated with such disadvantages. The present invention exploits the use of peptide analogues which antagonize a T cell response to human myelin basic protein to effectively treat MS, while providing other related advantages.
The present invention generally provides analogues of human myelin basic protein, in which the native L-lysine residue at position 91 is altered. Within one aspect of the invention, the analogue is a peptide derived from residues 87-99 of human myelin basic protein (MBP), wherein the L-lysine residue normally found at position 91 of native peptide is altered to another amino acid. The L-lysine residue at position 91 may be altered to any other amino acid, and preferably to alanine, serine, glycine, glutamic acid, phenylalanine, arginine, asparagine, histidine, leucine or D-lysine. The alteration is preferably a non-conservative change or any D-amino acid. The alteration is also preferably one which results in reduced production of TNF-xcex1 from MBP-reactive T cells.
The present invention provides a pharmaceutical composition comprising a peptide analogue according to the embodiments set out above, in which the analogue is contained in a physiologically acceptable carrier or diluent.
The present invention also provides methods for treating multiple sclerosis by administering to a patient with MS a therapeutically effective amount of a pharmaceutical composition containing analogue as described herein. As noted above, in one aspect a peptide analogue comprises amino acid residues 87-99 of human myelin basic protein, wherein the lysine at position 91 is replaced by another amino acid.
These and other aspects will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth below which describe in more detail certain procedures or compositions. Each of these references are incorporated herein by reference in their entirety as if each were individually noted for incorporation.